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JAMA Jul 2023Valganciclovir for 200 days is standard care for cytomegalovirus (CMV) prophylaxis in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a...
IMPORTANCE
Valganciclovir for 200 days is standard care for cytomegalovirus (CMV) prophylaxis in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor, but its use is limited by myelosuppression.
OBJECTIVE
To compare the efficacy and safety of letermovir with valganciclovir for prevention of CMV disease in CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor.
DESIGN, SETTING, AND PARTICIPANTS
Randomized, double-masked, double-dummy, noninferiority, phase 3 trial in adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor at 94 participating sites between May 2018 and April 2021 (final follow-up in April 2022).
INTERVENTIONS
Participants were randomized in a 1:1 ratio (stratified by receipt of lymphocyte-depleting induction immunosuppression) to receive letermovir, 480 mg, orally daily (with acyclovir) or valganciclovir, 900 mg, orally daily (adjusted for kidney function) for up to 200 days after transplant, with matching placebos.
MAIN OUTCOMES AND MEASURES
The primary outcome was CMV disease, confirmed by an independent masked adjudication committee, through posttransplant week 52 (prespecified noninferiority margin, 10%). CMV disease through week 28 and time to onset of CMV disease through week 52 were secondary outcomes. Exploratory outcomes included quantifiable CMV DNAemia and resistance. The rate of leukopenia or neutropenia through week 28 was a prespecified safety outcome.
RESULTS
Among 601 participants randomized, 589 received at least 1 dose of the study drug (mean age, 49.6 years; 422 [71.6%] men). Letermovir (n = 289) was noninferior to valganciclovir (n = 297) for prevention of CMV disease through week 52 (10.4% vs 11.8% of participants with committee-confirmed CMV disease; stratum-adjusted difference -1.4% [95% CI, -6.5% to 3.8%]). No participants who received letermovir vs 5 participants (1.7%) who received valganciclovir developed CMV disease through week 28. Time to onset of CMV disease was comparable between the groups (hazard ratio, 0.90 [95% CI, 0.56-1.47]). Quantifiable CMV DNAemia was detected in 2.1% of participants in the letermovir group vs 8.8% in the valganciclovir group by week 28. Of participants evaluated for suspected CMV disease or CMV DNAemia, none (0/52) who received letermovir and 12.1% (8/66) who received valganciclovir had resistance-associated substitutions. The rate of leukopenia or neutropenia through week 28 was lower with letermovir vs valganciclovir (26% vs 64%; difference, -37.9% [95% CI, -45.1% to -30.3%]; P < .001). Fewer participants in the letermovir group than the valganciclovir group discontinued prophylaxis due to adverse events (4.1% vs 13.5%) or drug-related adverse events (2.7% vs 8.8%).
CONCLUSION AND RELEVANCE
Among adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor, letermovir was noninferior to valganciclovir for prophylaxis of CMV disease over 52 weeks, with lower rates of leukopenia or neutropenia, supporting its use for this indication.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03443869; EudraCT: 2017-001055-30.
Topics: Adult; Male; Humans; Middle Aged; Female; Antiviral Agents; Valganciclovir; Cytomegalovirus; Kidney Transplantation; Cytomegalovirus Infections; Neutropenia
PubMed: 37279999
DOI: 10.1001/jama.2023.9106 -
Transplant International : Official... 2023Despite advances in monitoring and treatment, cytomegalovirus (CMV) infections remain one of the most common complications after solid organ transplantation (SOT). CMV... (Review)
Review
Despite advances in monitoring and treatment, cytomegalovirus (CMV) infections remain one of the most common complications after solid organ transplantation (SOT). CMV infection may fail to respond to standard first- and second-line antiviral therapies with or without the presence of antiviral resistance to these therapies. This failure to respond after 14 days of appropriate treatment is referred to as "resistant/refractory CMV." Limited data on refractory CMV without antiviral resistance are available. Reported rates of resistant CMV are up to 18% in SOT recipients treated for CMV. Therapeutic options for treating these infections are limited due to the toxicity of the agent used or transplant-related complications. This is often the challenge with conventional agents such as ganciclovir, foscarnet and cidofovir. Recent introduction of new CMV agents including maribavir and letermovir as well as the use of adoptive T cell therapy may improve the outcome of these difficult-to-treat infections in SOT recipients. In this expert review, we focus on new treatment options for resistant/refractory CMV infection and disease in SOT recipients, with an emphasis on maribavir, letermovir, and adoptive T cell therapy.
Topics: Humans; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Acetates; Ganciclovir
PubMed: 37901297
DOI: 10.3389/ti.2023.11785 -
The Journal of Clinical Investigation May 2024Herpesviruses establish latent infections, and most reactivate frequently, resulting in symptoms and virus shedding in healthy individuals. In immunocompromised... (Review)
Review
Herpesviruses establish latent infections, and most reactivate frequently, resulting in symptoms and virus shedding in healthy individuals. In immunocompromised patients, reactivating virus can cause severe disease. Persistent EBV has been associated with several malignancies in both immunocompromised and nonimmunocompromised persons. Reactivation and shedding occur with most herpesviruses, despite potent virus-specific antibodies and T cell immunity as measured in the blood. The licensure of therapeutic vaccines to reduce zoster indicates that effective therapeutic vaccines for other herpesviruses should be feasible. However, varicella-zoster virus is different from other human herpesviruses in that it is generally only shed during varicella and zoster. Unlike prophylactic vaccines, in which the correlate of immunity is antibody function, T cell immunity is the correlate of immunity for the only effective therapeutic herpesvirus vaccine-zoster vaccine. While most studies of therapeutic vaccines have measured immunity in the blood, cellular immunity at the site of reactivation is likely critical for an effective therapeutic vaccine for certain viruses. This Review summarizes the status of therapeutic vaccines for herpes simplex virus, cytomegalovirus, and Epstein-Barr virus and proposes approaches for future development.
Topics: Humans; Herpesvirus Vaccines; Herpesviridae Infections; Herpesvirus 4, Human; Animals; Herpesviridae; Virus Activation; Cytomegalovirus
PubMed: 38690731
DOI: 10.1172/JCI179483 -
Nature Feb 2024Individuals differ widely in their immune responses, with age, sex and genetic factors having major roles in this inherent variability. However, the variables that drive...
Individuals differ widely in their immune responses, with age, sex and genetic factors having major roles in this inherent variability. However, the variables that drive such differences in cytokine secretion-a crucial component of the host response to immune challenges-remain poorly defined. Here we investigated 136 variables and identified smoking, cytomegalovirus latent infection and body mass index as major contributors to variability in cytokine response, with effects of comparable magnitudes with age, sex and genetics. We find that smoking influences both innate and adaptive immune responses. Notably, its effect on innate responses is quickly lost after smoking cessation and is specifically associated with plasma levels of CEACAM6, whereas its effect on adaptive responses persists long after individuals quit smoking and is associated with epigenetic memory. This is supported by the association of the past smoking effect on cytokine responses with DNA methylation at specific signal trans-activators and regulators of metabolism. Our findings identify three novel variables associated with cytokine secretion variability and reveal roles for smoking in the short- and long-term regulation of immune responses. These results have potential clinical implications for the risk of developing infections, cancers or autoimmune diseases.
Topics: Female; Humans; Male; Adaptive Immunity; Autoimmune Diseases; Body Mass Index; Cytokines; Cytomegalovirus; DNA Methylation; Epigenesis, Genetic; Immunity, Innate; Infections; Neoplasms; Signal Transduction; Smoking
PubMed: 38355791
DOI: 10.1038/s41586-023-06968-8 -
Nature Nov 2023Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells...
Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are understudied. For example, we lack a comprehensive understanding of the mechanisms of toxicities observed in patients receiving T cell therapies, including recent reports of encephalitis caused by reactivation of human herpesvirus 6 (HHV-6). Here, through petabase-scale viral genomics mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in cultures of human CD4 T cells. Using single-cell sequencing, we identify a rare population of HHV-6 'super-expressors' (about 1 in 300-10,000 cells) that possess high viral transcriptional activity, among research-grade allogeneic chimeric antigen receptor (CAR) T cells. By analysing single-cell sequencing data from patients receiving cell therapy products that are approved by the US Food and Drug Administration or are in clinical studies, we identify the presence of HHV-6-super-expressor CAR T cells in patients in vivo. Together, the findings of our study demonstrate the utility of comprehensive genomics analyses in implicating cell therapy products as a potential source contributing to the lytic HHV-6 infection that has been reported in clinical trials and may influence the design and production of autologous and allogeneic cell therapies.
Topics: Humans; CD4-Positive T-Lymphocytes; Clinical Trials as Topic; Gene Expression Regulation, Viral; Genomics; Herpesvirus 6, Human; Immunotherapy, Adoptive; Infectious Encephalitis; Receptors, Chimeric Antigen; Roseolovirus Infections; Single-Cell Gene Expression Analysis; Viral Load; Virus Activation; Virus Latency
PubMed: 37938768
DOI: 10.1038/s41586-023-06704-2 -
Oncogene Jun 2023Mounting evidence is identifying human cytomegalovirus (HCMV) as a potential oncogenic virus. HCMV has been detected in malignant gliomas. EZH2 and Myc play a potential...
Mounting evidence is identifying human cytomegalovirus (HCMV) as a potential oncogenic virus. HCMV has been detected in malignant gliomas. EZH2 and Myc play a potential oncogenic role, correlating with the glioma grade. Herewith, we present the first experimental evidence for HCMV as a reprogramming vector, straight through the dedifferentiation of mature human astrocytes, and generation of CMV-Elicited Glioblastoma Cells (CEGBCs) possessing glioblastoma-like traits. HCMV counterparts the progression of the perceived cellular and molecular mechanisms succeeding the transformation and invasion processes with CEGBCs involved in spheroid formation and invasiveness. Glioblastoma multiforme (GBM) biopsies were characterized by an elevated EZH2 and Myc expression, possessing a strong positive correlation between the aforementioned markers in the presence of HCMV. From GBM tissues, we isolated HCMV clinical strains that transformed HAs toward CEGBCs exhibiting upregulated EZH2 and Myc. Spheroids generated from CEGBCs possessed invasion potential and were sensitive to EZH2 inhibitor, ganciclovir, and temozolomide triple therapy. HCMV clinical strains transform HAs and fit with an HCMV-induced glioblastoma model of oncogenesis, and supports the tumorigenic properties of Myc and EZH2 which might be highly pertinent in the pathophysiology of astrocytic brain tumors and thereby paving the way for new therapeutic strategies.
Topics: Humans; Astrocytes; Brain Neoplasms; Carcinogenesis; Cytomegalovirus; Cytomegalovirus Infections; Enhancer of Zeste Homolog 2 Protein; Glioblastoma; Proto-Oncogene Proteins c-myc
PubMed: 37147437
DOI: 10.1038/s41388-023-02709-3 -
Nature Sep 2023Humans display substantial interindividual clinical variability after SARS-CoV-2 infection, the genetic and immunological basis of which has begun to be deciphered....
Humans display substantial interindividual clinical variability after SARS-CoV-2 infection, the genetic and immunological basis of which has begun to be deciphered. However, the extent and drivers of population differences in immune responses to SARS-CoV-2 remain unclear. Here we report single-cell RNA-sequencing data for peripheral blood mononuclear cells-from 222 healthy donors of diverse ancestries-that were stimulated with SARS-CoV-2 or influenza A virus. We show that SARS-CoV-2 induces weaker, but more heterogeneous, interferon-stimulated gene activity compared with influenza A virus, and a unique pro-inflammatory signature in myeloid cells. Transcriptional responses to viruses display marked population differences, primarily driven by changes in cell abundance including increased lymphoid differentiation associated with latent cytomegalovirus infection. Expression quantitative trait loci and mediation analyses reveal a broad effect of cell composition on population disparities in immune responses, with genetic variants exerting a strong effect on specific loci. Furthermore, we show that natural selection has increased population differences in immune responses, particularly for variants associated with SARS-CoV-2 response in East Asians, and document the cellular and molecular mechanisms by which Neanderthal introgression has altered immune functions, such as the response of myeloid cells to viruses. Finally, colocalization and transcriptome-wide association analyses reveal an overlap between the genetic basis of immune responses to SARS-CoV-2 and COVID-19 severity, providing insights into the factors contributing to current disparities in COVID-19 risk.
Topics: Animals; Humans; Cell Differentiation; COVID-19; Cytomegalovirus; East Asian People; Genetic Introgression; Genetics, Population; Influenza A virus; Interferons; Leukocytes, Mononuclear; Myeloid Cells; Neanderthals; SARS-CoV-2; Selection, Genetic; Single-Cell Gene Expression Analysis; Virus Latency
PubMed: 37558883
DOI: 10.1038/s41586-023-06422-9 -
Frontiers in Cellular and Infection... 2023The human betaherpesviruses including human cytomegalovirus (HCMV), human herpesvirus (HHV)-6a and HHV-6b, and HHV-7 infect and establish latency in CD34+ hematopoietic... (Review)
Review
The human betaherpesviruses including human cytomegalovirus (HCMV), human herpesvirus (HHV)-6a and HHV-6b, and HHV-7 infect and establish latency in CD34+ hematopoietic stem and progenitor cells (HPCs). The diverse repertoire of HPCs in humans and the complex interactions between these viruses and host HPCs regulate the viral lifecycle, including latency. Precise manipulation of host and viral factors contribute to preferential maintenance of the viral genome, increased host cell survival, and specific manipulation of the cellular environment including suppression of neighboring cells and immune control. The dynamic control of these processes by the virus regulate inter- and intra-host signals critical to the establishment of chronic infection. Regulation occurs through direct viral protein interactions and cellular signaling, miRNA regulation, and viral mimics of cellular receptors and ligands, all leading to control of cell proliferation, survival, and differentiation. Hematopoietic stem cells have unique biological properties and the tandem control of virus and host make this a unique environment for chronic herpesvirus infection in the bone marrow. This review highlights the elegant complexities of the betaherpesvirus latency and HPC virus-host interactions.
Topics: Humans; Hematopoietic Stem Cells; Cytomegalovirus; MicroRNAs; Cell Differentiation; Cells, Cultured
PubMed: 37346032
DOI: 10.3389/fcimb.2023.1189805 -
Viruses Jun 2023Schizophrenia is a complex mental disorder with multiple genetic and environmental factors contributing to its pathogenesis. Viral infections have been suggested to be... (Review)
Review
Schizophrenia is a complex mental disorder with multiple genetic and environmental factors contributing to its pathogenesis. Viral infections have been suggested to be one of the environmental factors associated with the development of this disorder. We comprehensively review all relevant published literature focusing on the relationship between schizophrenia and various viral infections, such as influenza virus, herpes virus 1 and 2 (HSV-1 and HSV-2), cytomegalovirus (CMV), Epstein-Barr virus (EBV), retrovirus, coronavirus, and Borna virus. These viruses may interfere with the normal maturation of the brain directly or through immune-induced mediators, such as cytokines, leading to the onset of schizophrenia. Changes in the expression of critical genes and elevated levels of inflammatory cytokines have been linked to virally-induced infections and relevant immune activities in schizophrenia. Future research is necessary to understand this relationship better and provide insight into the molecular mechanisms underlying the pathophysiology of schizophrenia.
Topics: Humans; Schizophrenia; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Virus Diseases; Cytomegalovirus; Herpesvirus 2, Human
PubMed: 37376644
DOI: 10.3390/v15061345 -
Viruses Oct 2023Human Cytomegalovirus (HCMV) is a ubiquitous member of the Herpesviridae family, responsible for the most common congenital viral infection-congenital Cytomegalovirus... (Review)
Review
Human Cytomegalovirus (HCMV) is a ubiquitous member of the Herpesviridae family, responsible for the most common congenital viral infection-congenital Cytomegalovirus (cCMV) infection. While a majority of HCMV infections in children and adults are asymptomatic, HCMV is well known to cause severe infections in the immunocompromised individual and maternal infections with variable long-term sequelae after maternal-fetal transmission with primary or nonprimary infections. HCMV seroprevalence and cCMV incidence vary by geographic area and demographic characteristics like race and socioeconomic status. While cCMV birth prevalence ranges from 0.2% to 6% in different parts of the world, it is influenced by regional HCMV seroprevalence rates. HCMV screening during pregnancy is not routinely offered due to lack of awareness, hurdles to accurate diagnosis, and lack of well-established effective treatment options during pregnancy. This review will focus on antiviral treatment options currently available for use during pregnancy and in the newborn period for the treatment of maternal and congenital HCMV infections.
Topics: Infant, Newborn; Pregnancy; Adult; Child; Female; Humans; Cytomegalovirus; Seroepidemiologic Studies; Cytomegalovirus Infections; Family; Infectious Disease Transmission, Vertical; Antiviral Agents; Pregnancy Complications, Infectious
PubMed: 37896892
DOI: 10.3390/v15102116